Modeling the genetic basis for human congenital heart disease in mice

在小鼠中模拟人类先天性心脏病的遗传基础

基本信息

  • 批准号:
    8518108
  • 负责人:
  • 金额:
    $ 160.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Congenital heart disease (CHD) affects up to 1% of live births, but its genetic basis is still not well understood. Human studies to unravel the genetic causes of CHD is challenging given genetic diversity of the human population. Genetic analysis in mice is advantageous given the mouse genome is completely sequenced, and inbred mice provide animals that are genetically identical. Knockout mouse studies have identified many genes that can cause CHD. However, ftjnctional redundancies may mask gene function or early embryonic lethality may preclude assessment of CHD. We propose a complementary approach with forward genetic screening with ethylnitrosourea mutagenesis to recover mutations causing CHD. We previously showed noninvasive mouse fetal echocardiography is highly effective for high throughput Cardiovascular phenotyping. Our screen recovered many genes encoding proteins in the cilia or centrosome, suggesting the cilium is a central disease pathway in CHD. To recover mutations causing CHD, we plan to use noninvasive fetal echocardiography to screen 100,000 mouse fetuses from 4000 pedigrees to achieve an estimated five-fold genome coverage (Aim 1). We will use a two-tier approach with high throughput targeted and whole genome DNA sequencing to identify the mutations (Aim 2). For genes suspected to have a role in the cilium, zebrafish will be used for rapid morpholino knock-down to analyze the motiie/nonmotile functions of the cilia and possible disruption of left-right patteming related to cilia defects (Aim 3). Mouse embryonic fibroblasts and tissues derived from mutant embryos will be used to evaluate cell-intrinsic function related to the cilium and centrosome (Aim 4). To elucidate the role of the cilia in cardiac morphogenesis, mutant embryos will be examined for heart looping, deployment of extracardiac cell populations to the heart, outflow tract and chamber septation. Cilia mediated sonic hedgehog and non-canonical Wnt signaling also ^ili be examined (Aim 5). In summary, the proposed studies will help elucidate the genetic basis for CHD. Many new CHD mouse models will be generated and the role of the cilium and other pathways playing important roles in CHD will emerge with the identification of a core set of genes critically involved in CHD. RELEVANCE (See instructions); The identification of a core set of genes involved in congenital heart disease can provide the basis for future translational studies with human subjects to elucidate the complex genetics of human congenital heart disease. This could include the design of diagnostic chips for genotyping patients with congenital heart disease and examining for correlation between genotype with disease phenotype and long term outcome.
描述(由申请人提供):

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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CECILIA W. LO其他文献

CECILIA W. LO的其他文献

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{{ truncateString('CECILIA W. LO', 18)}}的其他基金

Mechanism of LV Hypoplasia in Hypoplastic Left Heart Syndrome Supplement
左心发育不全综合征补充剂中左室发育不全的机制
  • 批准号:
    10091850
  • 财政年份:
    2018
  • 资助金额:
    $ 160.53万
  • 项目类别:
Mechanism of LV Hypoplasia in Hypoplastic Left Heart Syndrome
左心发育不良综合征中左室发育不全的机制
  • 批准号:
    9922704
  • 财政年份:
    2018
  • 资助金额:
    $ 160.53万
  • 项目类别:
Mechanism of LV Hypoplasia in Hypoplastic Left Heart Syndrome
左心发育不良综合征中左室发育不全的机制
  • 批准号:
    10426568
  • 财政年份:
    2018
  • 资助金额:
    $ 160.53万
  • 项目类别:
Mechanism of LV Hypoplasia in Hypoplastic Left Heart Syndrome
左心发育不良综合征中左室发育不全的机制
  • 批准号:
    10206242
  • 财政年份:
    2018
  • 资助金额:
    $ 160.53万
  • 项目类别:
Modeling the complex genetics of congenital heart disease in mice
模拟小鼠先天性心脏病的复杂遗传学
  • 批准号:
    9260066
  • 财政年份:
    2016
  • 资助金额:
    $ 160.53万
  • 项目类别:
Confocal enhanced episcopic fluorescent image capture (EFIC)
共焦增强型落射荧光图像捕获 (EFIC)
  • 批准号:
    8246865
  • 财政年份:
    2012
  • 资助金额:
    $ 160.53万
  • 项目类别:
WHOLE GENOME ASSEMBLY FROM NEXTGEN SEQUENCING SHORT READ DATA
来自下一代测序短读数据的全基因组组装
  • 批准号:
    8364347
  • 财政年份:
    2011
  • 资助金额:
    $ 160.53万
  • 项目类别:
Modeling the genetic basis for human congenital heart disease in mice
在小鼠中模拟人类先天性心脏病的遗传基础
  • 批准号:
    7769366
  • 财政年份:
    2009
  • 资助金额:
    $ 160.53万
  • 项目类别:
Modeling the genetic basis for human congenital heart disease in mice
在小鼠中模拟人类先天性心脏病的遗传基础
  • 批准号:
    8127905
  • 财政年份:
    2009
  • 资助金额:
    $ 160.53万
  • 项目类别:
Modeling the genetic basis for human congenital heart disease in mice
在小鼠中模拟人类先天性心脏病的遗传基础
  • 批准号:
    7936085
  • 财政年份:
    2009
  • 资助金额:
    $ 160.53万
  • 项目类别:

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